COMPARATIVE EFFECTIVENESS OF VEDOLIZUMAB AND USTEKINUMAB IN CROHN’S DISEASE: INSIGHTS FROM A REAL-WORLD SURVIVAL ANALYSIS

Abstract Background And Objectives Vedolizumab, an anti-integrin agent, and ustekinumab, an anti-IL12/23 monoclonal antibody, are established biologics for moderate-to-severe Crohn’s disease. Despite increasing utilization, real-world comparative effectiveness data remain limited, particularly regarding long-term clinical outcomes, safety events, and biomarker normalization patterns. We aimed to compare these agents across comprehensive clinical, safety, and laboratory endpoints using a large federated electronic health record network. METHODS This retrospective cohort study utilized the TriNetX US Collaborative Network encompassing 69 healthcare organizations. Adult patients (≥18 years) with Crohn’s disease initiating vedolizumab (n = 4,697) or ustekinumab (n = 10,771) with ≥3-month washout from aminosalicylates were included. Rigorous propensity score matching (1:1) balanced demographics, comorbidities, and prior medication exposure, yielding 4,567 matched pairs. Primary and secondary outcomes were assessed over 3 years using Kaplan-Meier survival analysis, hazard ratios (HR), and 95% confidence intervals (CI) with log-rank testing. RESULTS Vedolizumab demonstrated significant advantages in procedural outcomes: reduced outpatient visits (HR 0.50; 95% CI 0.40-0.63; p < 0.001), stricturoplasty/dilation procedures (HR 0.62; CI 0.43-0.87; p = 0.006), fistulectomy (HR 0.60; CI 0.37-0.97; p = 0.036), and perianal abscess drainage (HR 0.58; CI 0.35-0.98; p = 0.038). However, vedolizumab was associated with significantly higher all-cause mortality (HR 1.47; CI 1.09-1.97; p = 0.010) and multiple safety concerns: thrombocytopenia (HR 1.83; CI 1.28-2.61; p = 0.001), sepsis (HR 1.36; CI 1.05-1.75; p = 0.019), pneumonia (HR 1.41; CI 1.07-1.85; p = 0.013), and Clostridioides difficile infection (HR 1.50; CI 1.04-2.16; p = 0.028). Hospitalization rates, emergency visits, and IBD surgery showed no significant differences. Ustekinumab demonstrated superior systemic inflammation control with lower rates of elevated CRP ≥10 mg/L (HR 1.17; CI 1.01-1.35; p = 0.033) and hypoalbuminemia < 3.5 g/dL (HR 1.24; CI 1.07-1.44; p = 0.005). Conversely, vedolizumab achieved better fecal calprotectin normalization < 150 μg/g (HR 0.85; CI 0.75-0.97; p = 0.017), suggesting superior local intestinal inflammation control. CONCLUSIONS Both agents exhibit distinct therapeutic profiles with complementary advantages. Vedolizumab may be preferred for patients at high risk for surgical complications but carries increased infectious and hematologic risks. Ustekinumab demonstrates superior systemic inflammation control with a potentially safer profile. These real-world findings support individualized treatment selection based on patient-specific risk factors and warrant confirmatory prospective head-to-head trials.